Tubular maximum for calcium reabsorption: Lack of diagnostic usefulness in primary hyperparathyroidism and familial hypocalciuric hypercalcaemia

Clinica Chimieu Acru, 166 (1987) 155-161 Elsevier

155

CCA 03808

Tubular maximum for calcium reabsorption: lack of diagnostic usefulness in primary hyperparathyroidism and familial hypocalciuric hypercalcaemia G. Neil Kent ‘, Chotoo I. Bhagat b, Peter Garcia-Webb and Donald H. Gutte~dge a

’

a Department of Endocrinoiogv and Diabetes, Sir Charles Gairdner Hospital, Perth. ’ Combined Clinrcal Biochemistry Service, Queen Elizabeth II Medical Centre, Perth and ’ Department of Clinical BiochemistT, Umversity of Western Ausrralia, Perth (Western Austrulia) (Received 20 August 1986; revision received and accepted 18 February 1987)

Key words: Maximum tubular reabsorption; Calcium; Primary hype~arathyroidism; Familial hypocaiciuric hypercakemia; Fasting calcium excretion

Summary The theoretical tubular maximum for calcium reabsorption was calculated and its usefulness assessed in the diagnosis and differential diagnosis of primary hyperp~athyroidism and familial hyp~~~u~c hyperc~cae~a. The sensitivity of the test in the diagnosis of primary h~e~arathyroidism was only 12%. The theoretical tubular maximum for calcium reabsorption was recalculated after correction of calcium concentration in plasma for albumin concentration and for urinary sodium excretion. Despite these corrections, the sensitivity improved to only 44%. This contrasts with a sensitivity of 80% for the plot of fasting calcium excretion against calcium concentration in plasma in primary hyperparathyroidism. The calculation of theoretical tubular maximum for calcium reabsorption cannot be recommended as a useful test for distinguis~g between primary hype~arathyroidism and familial hypocalciuric hypercalcaemia. The simple calculation of fractional excretion of calcium was a better test in distinguishing familial hypocalciuric hypercalcaemia from primary hyperparathyroidism.

Correspondence to: Dr. N. Kent, Department of End~nology Hospital, Nedfands, Western Australia 6009. 0009-8981/87/$03.50

and Diabetes, Sir Charles Gairdner

0 1987 Elsevier Science Publishers B.V. (Biomedical Division)

156

Introduction

The diagnosis of primary hyperparathyroidism (HPT) and familial hypocalciuric hypercalcaemia (FHH) depends, at least in part, on the measurement of an index of renal tubular reabsorption of calcium. Tubular reabsorption of calcium, and more so urinary calcium excretion, varies with plasma calcium concentration. In view of this a number of approaches have been used to relate calcium handling by the kidney to plasma calcium concentration. Recently a method for calculating the theoretical maximum tubular reabsorption of calcium (TmCa) relative to the glomerular filtration rate was reported in 130 healthy subjects [l]. In that paper it was suggested that TmCa corrected for sodium excretion in urine and/or for albumin concentration in plasma could be of use in a variety of clinical situations including HPT and FHH. The purpose of this paper is to compare the diagnostic usefulness of TmCa with other more standard tests of calcium metabolism in the diagnosis and differential diagnosis of primary hyperparathyroidism and familial hypocalciuric hypercalcaemia. Methods

Calcium, sodium, albumin, creatinine and inorganic phosphate in heparinized plasma were measured promptly using Technicon (Tarrytown, NY, USA) methods on a SMAC II analyser. Calcium, sodium, creatinine and inorganic phosphate in urine were measured using Technicon methods on a RA-1000 analyser. Serum (separated at room temperature, stored at - 20 o C) immunoreactive parathyroid hormone (iPTH) was measured by radioimmunoassay using a mid-molecule region specific antibody (AS-17, from the Institut National des Radioelements, Fleuris. Belgium) [2]. Cyclic adenosine monophosphate (CAMP) in urine was measured by an in house radioimmunoassay modified from Steiner et al [3]. Total urinary CAMP excretion was expressed as nmol/l glomerular filtrate (GF) as described [4]. The theoretical TmCa was calculated using the formula: TmCa = [(0.56 PCs) Ca,]/[l - 0.08 logJO. PCa/Ca,)] mmol/l GF, as described [l]), where P indicates concentration in plasma. The calcium excretion per litre of glomerular filtrate was calculated using the formula Ca, = [(UCa/UCr) X PCr] where U indicates concentration in urine and Cr stands for creatinine. The sodium excretion per litre of glomerular filtrate was calculated as Na, = [(UNa/UCr) x PCr]. F rat t’lonal excretion of calcium was calculated as FExCa = [UCa x PCr x lOO]/[UCr x PCs]. The renal threshold inorganic phosphate concentration (TmPi/GFR) was calculated from the nomogram of Walton and Bijvoet

[51. Calcium concentration in plasma was corrected for albumin concentration using the formula PCs + [(40-albumin) x 0.021 where albumin is in g/l [6]. The TmCa corrected for albumin {TmCa (alb corr)} was calculated by substituting the corrected calcium concentration in the formula for TmCa. The TmCa corrected for urinary sodium excretion {TmCa (Na corr)} was calculated using our control

157

subject data as TmCa (Na corr) = [TmCa + (0.274 X Nan)] as described [l]. Finally, TmCa was calculated correcting for both albumin concentration in plasma and sodium excretion {TmCa (Alb, Na corr)}. Subjects Three groups of individuals were studied: group 1 comprised 59 healthy individuals thought to be free of any disease likely to affect calcium homeostasis or renal function. Group 2 comprised 41 patients with HPT in whom the diagnosis was subsequently confirmed by surgery and microscopy of the excised parathyroid tissue. Twelve of the patients were being treated with diuretics, steroids or oestrogen. These drugs were withheld for at least 24 h before the test. Separate analysis of data from these twelve subjects indicated that they were not different from the rest of the group and so the data were pooled. Group 3 comprised 17 patients diagnosed as having FHH according to the criteria recommended by Marx [7]. Urine was collected for 2 h and a sample of blood was taken at the midpoint of the urine collection from individuals who had fasted overnight and had been sitting for 30 min [8]. Results

Table I shows the mean and range for each of the measured and calculated variables for the three groups. It is apparent that there was considerable overlap between the results from the groups.

TABLE

I

Mean and range for a number parathyroidism (HPT) or familial Control Mean

of variables hypocalciuric

in control subjects and hypercalcaemia (FHH)

(n = 59)

HPT(n

k2SD

Mean

range TmCa mmol/l GF TmCa (alb corr) mrnol/l GF TmCa (Na corr) mmol/l GF TmCa (alb. Na corr) mmol/l GF TmPi/GFR mmol/l GF Serum iPTH pmol/l Urine CAMP nmol/l GF

patients

= 41)

with

primary

hyper-

FHH (n = 17)

Observed range

Mean

Observed range

2.03

1.58-

2.48

2.24

1.82-

2.75

2.62

2.21-

3.16

1.95

1.58-

2.33

2.20

1.82-

2.72

2.52

2.15-

2.94

2.26

1.90-

2.61

2.56

2.19-

3.17

2.83

2.41-

3.33

2.15

1.84-

2.46

2.46

2.09-

3.10

2.69

2.32-

3.09

1.06

0.78-

1.35

0.68

0.27-

1.10

0.85

0.65-

1.10

<40 25

Serum iPTH is expressed as pmol filtrate. Abbreviations are explained

11

-39

of a synthetic in text.

186

11

-741

32

10

-61

47

24

- 89

29

20

-40

standard

(human

PTH

(4468)).

GF is glomerular

158 TABLE Sensitivity

II of a number

of variables

in the diagnosis of primary hyperparathyroidism

(HPT) and familial

hypocalciuric hypercalcaemia (FHH)

HPT (I) (n = 41)

FHH (%) (n =17)

TmCa TmCa (alb corr) TmCa (Na corr) TmCa (alb. Na corr) Ca, plot TmPi/GFR Serum iPTH

12 24 37 44 80 56 85

76 82 88 94 100 47 12

Urine CAMP

58

6

Data are sensitivity calculated subjects with disease expressed

as the number as a percentage.

2.0

of subjects with positive result divided Abbreviations are explained in text.

by number

of

3.0 Plasma

Calcium

( mmol/L

)

Fig. 1. Fasting calcium excretion and fasting plasma calcium concentration in patients with primary hyperparathyroidism (A) and familial hypocalciuric hypercalcaemia (0). The mean and * 2 SD curves were recalculated

in SI units from Nordin

et al 191.

159

The sensitivity for the diagnosis of hyperparathyroidism and familial hypocalciuric hypercalcaemia was calculated for each of the tests (number of subjects with positive result divided by the number of subjects with disease). A positive result was taken to be a result outside the reference range. Sensitivities are shown in Table II. Ca, was plotted against the calcium concentration of plasma [8]. Sensitivity for this plot was calculated with positive results lying to the right-hand side of -2 SD curve in Fig. 1. Discussion

The results of TmCa, TmCa (Na corr) and TmCa (Alb, Na corr) for our control subjects (Table I) were similar to those obtained by Need et al [l]. Primary hyperparathyroidism

Need et al state that TmCa is generally raised in primary hyperparathyroidism [l]. The statement is supported by a reference to a textbook published in 1976 [9]. However, the textbook statement was made with no apparent reference to patient data. Only 5 out of 41 patients (12%) with HPT gave a positive result for TmCa uncorrected for plasma albumin or urine sodium excretion. The sensitivity of the test was increased by adjusting TmCa for the effects of these variables either singly or in combination (Table II). Nevertheless, there was still considerable overlap between the control subjects and patients with HPT (Fig. 2). The maximum sensitivity achieved for TmCa corrected for both sodium and albumin was only 44%. For comparison, the sensitivity of TmPi/GFR was 56% and that for total urinary cyclic AMP was 58%. Plotting Ca, against the calcium concentration of plasma gave a sensitivity of 80% and the measurement of parathyroid hormone provided a sensitivity of 85%. Thus each of the tests currently accepted as being of use in the differential diagnosis of hyperparathyroidism had a greater sensitivity than TmCa corrected for both sodium and albumin. Familial hypocalciuric hypercalcaemia

The sensitivity of uncorrected TmCa for the diagnosis of FHH was 76% and that of TmCa corrected for both sodium and albumin was 94%. It might seem therefore that this is a useful test to use in trying to diagnose that condition. However the plot of Ca, against the calcium concentration of plasma (Fig. 1) had a sensitivity of 100%. Differential diagnosis of HPT and FHH

The problem in the diagnosis of FHH is not simply that of confirming that the urine excretion of calcium is low (or that tubular reabsorption is high) having regard for the plasma concentration of calcium. Instead the difficulty for the clinician is to

160

HPT

FHH

3.0 -

HPT

FHH

.

.

’ 1

. : . . . i r,

.

Fig. 2. Fractional excretion of calcium [FExCa] and tubular maximum for calcium reabsorption corrected for both plasma albumin concentration and urinary sodium excretion [TmCa(alb, Na corr)] in patients with primary hyperparathyroidism (HFT’) and familial hypocalciuric hypercalcaemia (FHH). Hatched area denotes reference range.

distinguish patients with FHH from those with HPT. Such a distinction requires consideration of plasma PTH, urine CAMP, TmPi/GFR together with the demonstration of an abnormality in calcium metabolism in other members of the family

[W Need et al were of the view that TmCa would have better sensitivity than fractional excretion of calcium in the diagnosis of FHH [l]. That suggestion is confirmed by the present study since the sensitivity of FExCa for the diagnosis of FHH was only 12% compared with 94% for TmCa corrected for both sodium and albumin. However this does not imply that TmCa is clinically useful. Thus there is a large overlap between results for TmCa corrected for both sodium and albumin in patients with FHH and HPT (Fig. 2). However for FExCa, the overlap is much less. Thus a cut-off point of 0.5% for FExCa distinguishes 16 out of 17 patients with FHH from 36 out of 41 patients with HPT. We have not investigated the clinical application of TmCa in such conditions as sarcoidosis or vitamin D intoxication. However, the results reported here indicate that the complex calculation of TmCa with or without correction for sodium and albumin has no place in the differential diagnosis of HPT. TmCa results are greater than the reference range~in familial hypocalciuric hypercalcaemia, but the test is of little value in distinguishing patients with that disease from patients with HPT. On this basis, the calculation of TmCa cannot be recommended as a useful test in these clinical situations.

161

References 1 Need AG, Guerin MD, Pain RW, Hartley TF, Nordin BEC. The tubular maximum for calcium reabsorption: normal range and correction for sodium excretion. Clin Chim Acta 1985;150:87-93. 2 Worth GK, Nicholson GC, Retallack RW, Gutteridge DH, Kent JC. Parathyroid hormone radioimmunoassay: the clinical evaluation of assays using commercially available reagents. J Immunoassay 1985;6:277-298. 3 Steiner AL, Parker CW, Kipnis DM. Radioimmunoassay for cyclic nucleotides. I. Preparation of antibodies and iodinated cyclic nucleotides. J Biol Chem 1972;247:1106-1113. 4 Broadus AE. Nephrogenous cyclic AMP. Recent Prog Horm Res 1981;37:667-701. 5 Walton RJ, Bijvoet OLM. Nomogram for derivation of renal threshold phosphate concentration. Lancet 1975;2:309-310. 6 Editorial. Serum-calcium. Lancet 1979;1:858-859. 7 Marx SJ. Familial hypocalciuric hypercalcaemia. N Engl J Med 1980;303:810-811. 8 Nordin BEC. Diagnostic procedures in disorders of calcium metabolism. Clin Encocrinol 1978;8:55-67. 9 Nordin BEC, Horsmann A, Aaron J. Diagnostic procedures. In: Nordin BEC, ed. Calcium, phosphate and magnesium metabolism. Edinburgh: Churchill Livingstone, 1976;469-524. 10 Marx SJ, Spiegel AM, Brown EM, et al. Circulating parathyroid hormone activity: familial hypocalciuric hypercalcaemia versus typical primary hyperparathyroidism. J Clin Endocrinol Metab 1978;47:1190-1197.